title: SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling.
abstract: The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85α regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85α and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling.
authors.affiliation: K.G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway.
authors.forename: Kishan Kumar
authors.initials: KK
authors.lastname: Chudasama
authors.forename: Jonathon
authors.initials: J
authors.lastname: Winnay
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.forename: Tor
authors.initials: T
authors.lastname: Claudi
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.forename: Ingfrid
authors.initials: I
authors.lastname: Haldorsen
authors.forename: Bente
authors.initials: B
authors.lastname: Johansson
authors.forename: Ju Rang
authors.initials: JR
authors.lastname: Woo
authors.forename: Dagfinn
authors.initials: D
authors.lastname: Aarskog
authors.forename: Jørn V
authors.initials: JV
authors.lastname: Sagen
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Pål Rasmus
authors.initials: PR
authors.lastname: Njølstad
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015992:Body Mass Index; D002454:Cell Differentiation; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population / Q000379:methods; D006130:Growth Disorders / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D006934:Hypercalcemia / Q000201:enzymology* / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000201:enzymology* / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009397:Nephrocalcinosis / Q000201:enzymology* / Q000473:pathology; D010375:Pedigree; D015398:Signal Transduction; D055815:Young Adult; D018909:src Homology Domains
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D058543:Class Ia Phosphatidylinositol 3-Kinase